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Contribution of airway eosinophils in airway wall remodeling in asthma: role of MMP-10 and MET

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Title: Contribution of airway eosinophils in airway wall remodeling in asthma: role of MMP-10 and MET
Authors: Kuo, C-HS
Pavlidis, S
Zhu, J
Loza, M
Baribaud, F
Rowe, A
Pandis, I
Gibeon, D
Hoda, U
Sousa, A
Wilson, SJ
Howarth, P
Shaw, D
Fowler, S
Dahlen, B
Chanez, P
Krug, N
Sandstrom, T
Fleming, L
Corfield, J
Auffray, C
Djukanovic, R
Sterk, PJ
Guo, Y
Adcock, IM
Chung, KF
U-BIOPRED Project Team
Item Type: Journal Article
Abstract: Background Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. Methods We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate‐to‐severe asthma of the U‐BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Results Using stringent false discovery rate analysis, MMP‐10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP‐10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less‐stringent conditions (raw P‐value < 0.05, log2 fold change > 0.5), we defined a 73‐gene set characteristic of the HE compared to the LE group. Thirty‐three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC‐chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS‐1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Conclusion Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP‐10 likely play an important role in these processes.
Issue Date: 11-Feb-2019
Date of Acceptance: 21-Jan-2019
URI: http://hdl.handle.net/10044/1/67192
DOI: https://dx.doi.org/10.1111/all.13727
ISSN: 0105-4538
Publisher: Wiley
Journal / Book Title: Allergy
Copyright Statement: © 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. This is the accepted version of the following article, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/all.13727
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 115010
Keywords: MET
MMP10
asthma
eosinophil
mast cell
U-BIOPRED Project Team
1107 Immunology
Allergy
Publication Status: Published online
Embargo Date: 2020-01-22
Online Publication Date: 2019-01-22
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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